Correlation between 5-HT7 receptor affinity and protection against sound-induced seizures in DBA/2J mice

Naunyn Schmiedebergs Arch Pharmacol. 1997 Dec;356(6):820-6. doi: 10.1007/pl00005123.

Abstract

Audiogenic seizures can be induced in DBA/2J mice following intense auditory stimulation. A number of neurotransmitters, including 5-hydroxytryptamine (5-HT), are believed to be involved in mediating this effect since it has been shown previously that depletion of 5-HT or blockade of 5-HT receptors protects DBA/2J mice from these audiogenic seizures. The present study was undertaken to determine whether antagonism of the newly identified 5-HT7 receptor may protect DBA/2J mice from audiogenic seizures by attempting to correlate in vivo potency of compounds with their affinity at the 5-HT7 receptor. All compounds used in the correlation were shown to be antagonists at the 5-HT7 receptor and a statistically significant correlation was observed between 5-HT7 affinity and doses for half-maximal response (ED50) for protection of DBA/2J mice from sound-induced seizures (r = 0.80; P < 0.05). No significant correlation was observed between in vivo activity and affinity at either 5-HT1A, 5-HT2A or 5-HT2C receptors. It is also unlikely that interactions between the 5-ht5 receptor will protect DBA/2J mice from audiogenic seizures since metergoline and mesulergine which are both active in this in vivo model have no affinity for the 5-ht5 receptor. There are similarities between the pharmacology of the 5-HT7 receptor and that of the 5-HT1A receptor, however the correlation between the in vivo potency in DBA/2J mice and 5-HT1A affinity was not significant. Furthermore, the 5-HT1A receptor antagonist WAY 100135 did not protect DBA/2J mice from audiogenic seizures at doses that antagonise 5-HT1A receptor-mediated effects in mice. These data suggest that antagonism of 5-HT7 receptors may protect against audiogenic seizures in DBA/2J mice although a definitive conclusion must await studies with selective 5-HT7 antagonists.

Publication types

  • Comparative Study

MeSH terms

  • Acoustic Stimulation
  • Animals
  • Anticonvulsants / metabolism
  • Anticonvulsants / therapeutic use*
  • CHO Cells
  • Cricetinae
  • Ergolines / metabolism
  • Ergolines / therapeutic use
  • Male
  • Methysergide / metabolism
  • Methysergide / therapeutic use
  • Mianserin / metabolism
  • Mianserin / therapeutic use
  • Mice
  • Mice, Inbred DBA
  • Receptors, Serotonin / drug effects
  • Receptors, Serotonin / metabolism*
  • Seizures / etiology
  • Seizures / prevention & control*
  • Serotonin Antagonists / metabolism
  • Serotonin Antagonists / therapeutic use*

Substances

  • Anticonvulsants
  • Ergolines
  • Receptors, Serotonin
  • Serotonin Antagonists
  • serotonin 7 receptor
  • Mianserin
  • mesulergine
  • Methysergide